Structure-activity relationship for nucleoside analogs as inhibitors or substrates of adenosine kinase from Mycobacterium tuberculosis. I. Modifications to the adenine moiety

Biochemical Pharmacology
Mary C Long, William B Parker

Abstract

Adenosine kinase (Ado kinase, EC 2.7.1.20) is a purine salvage enzyme that phosphorylates adenosine (Ado) to AMP. Ado kinase from Mycobacterium tuberculosis also catalyzes an essential step in the conversion of 2-methyl-Ado to a compound with selective antimycobacterial activity. In order to aid in the design of more potent and selective Ado analogs, eighty nucleoside analogs with modifications to the adenine (Ade) moiety of Ado were evaluated as both substrates and inhibitors of Ado kinase from M. tuberculosis, and a subset was further tested with human Ado kinase for the sake of comparison. The best substrates were 2-aza-Ado, 8-aza-9-deaza-Ado, and 2-fluoro-Ado and the most potent inhibitors were N1-benzyl-Ado (Ki=0.19 microM), 2-fluoro-Ado (Ki=0.5 microM), 6-cyclopentyloxy-purine riboside (Ki=0.15 microM), and 7-iodo-7-deaza-Ado (Ki=0.21 microM). These studies revealed the presence of a hydrophobic pocket near the N6- and N1-positions that can accommodate substitutions at least as large as a benzyl group. The ability to fit into this pocket increased the likelihood that a compound would be an inhibitor and not a substrate. The 2-position was able to accommodate exocyclic substitutions as large as a methoxy group, although su...Continue Reading

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Citations

Jan 1, 2013·Acta Crystallographica. Section D, Biological Crystallography·Larissa RomanelloHumberto D'Muniz Pereira
Jun 27, 2013·MBio·Anand SrinivasanAnand K Ramasubramanian
Aug 1, 2008·Expert Review of Respiratory Medicine·Haruaki TomiokaToshiaki Shimizu
Jan 1, 2012·Pharmaceuticals·Neeraj ShakyaRakesh Kumar
Jun 10, 2009·FEBS Letters·Jae ParkRadhey S Gupta
Apr 18, 2013·Pharmacological Reviews·Detlev Boison
Nov 16, 2019·Chemical Communications : Chem Comm·Sisi GaoJames H Naismith
Sep 9, 2010·ACS Medicinal Chemistry Letters·Patrice MarchandLouisa Barré
Feb 13, 2007·Bioorganic & Medicinal Chemistry·Yves L Janin
Mar 24, 2007·Bioorganic & Medicinal Chemistry Letters·Sidath C KumarapperumaJeffrey B Arterburn

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